Two major problems pertaining to current efforts to develop clinical pneumococcal polysaccharide-protein vaccines are: 1) variation in the immunogenicity of conjugate vaccines even when the carrier remains the same and 2) the unpredictable effects of carrier priming including suppression of the anti-polysaccharide antibody response in some cases. The proposed studies are designed to elucidate the immunologic mechanisms responsible for variation in polysaccharide-protein conjugate immunogenicity when different polysaccharides are coupled to the same carrier and to determine conditions that maximize the ability of carrier priming to boost the protective antibody response to subsequent polysaccharide-carrier immunizations. In Specific Aim 1, variations in immunogenicity of three pneumococcal polysaccharide-protein conjugates will be documented by assays of serum antibody and T cell responsiveness in mice. In Specific Aim 2, the influence of the polysaccharide in altering processing of the carrier protein by class II MHC molecules will be determined. A second aspect of Specific Aim 2 involves the role of Ps-specific precursor frequency in the induction of the immune response to the polysaccharide-protein conjugate. In Specific Aim 3, the roles of different types of antigen presenting cells (activated B cells, macrophages, and dendritic cells) and the patterns of T cell-derived cytokines elicited by the different antigen-presenting cells will be analyzed.